Origin of the E/Z Selectivity in the Synthesis of Tetrasubstituted Olefins by Wittig Reaction of α-Fluorophosphonium Ylides: An Explanation for the Low Stereoselectivity Observed in Reactions of α-Alkoxy Aldehydes.

A series of tetrasubstituted fluoroalkenes were synthesized in good yield and high E/Z selectivity (up to 96/4) by Wittig reaction between α-heterosubstituted ketones and α-fluorophosphonium ylides. A detailed study of factors that control stereoselectivity in these reactions shows that stereoselectivity is the result of stabilizing CH···F and N···C═O interactions in the addition TS leading to the E isomer. This analysis provides a rationale for the observed decrease in selectivity for reactions of stabilized ylides with α-alkoxy aldehydes.

[1]  A. Vulpetti,et al.  Weak Intermolecular Hydrogen Bonds with Fluorine: Detection and Implications for Enzymatic/Chemical Reactions, Chemical Properties, and Ligand/Protein Fluorine NMR Screening. , 2016, Chemistry.

[2]  Zhuo Chen,et al.  Isotope Effects, Dynamic Matching, and Solvent Dynamics in a Wittig Reaction. Betaines as Bypassed Intermediates , 2014, Journal of the American Chemical Society.

[3]  Peter A Byrne,et al.  Unequivocal experimental evidence for a unified lithium salt-free Wittig reaction mechanism for all phosphonium Ylide types: reactions with β-heteroatom-substituted aldehydes are consistently selective for cis-oxaphosphetane-derived products. , 2012, Journal of the American Chemical Society.

[4]  A. Flynn,et al.  Stereocontrolled synthesis of tetrasubstituted olefins. , 2007, Chemical reviews.

[5]  M. Peterson,et al.  Stereochemistry and Mechanism in the Wittig Reaction , 2007 .

[6]  J. Harvey,et al.  Reactivity and selectivity in the Wittig reaction: a computational study. , 2006, Journal of the American Chemical Society.

[7]  J. Harvey,et al.  On the origin of high E selectivity in the Wittig reaction of stabilized ylides: importance of dipole-dipole interactions. , 2005, Journal of the American Chemical Society.

[8]  Gautam R Desiraju,et al.  C-H...O and other weak hydrogen bonds. From crystal engineering to virtual screening. , 2005, Chemical communications.

[9]  S. Scheiner,et al.  CH···F Hydrogen Bonds. Dimers of Fluoromethanes , 2004 .

[10]  K. Nicolaou,et al.  The Wittig and Related Reactions in Natural Product Synthesis , 1997 .

[11]  A. Reitz,et al.  The Wittig olefination reaction and modifications involving phosphoryl-stabilized carbanions. Stereochemistry, mechanism, and selected synthetic aspects , 1989 .

[12]  O. Vostrowsky,et al.  Selected topics of the wittig reaction in the synthesis of natural products , 1983 .